1. Field of the Invention
The present invention relates to compounds that act, at physiologically-compatible levels, to impede the formation of amyloid in brain, including Alzheimer senile amyloid plaques in vivo. More specifically, the present invention relates to compounds that impede the transformation of dense microspheres (DMS) into amyloid. The invention also relates to methdology for the screening of compounds that possess this activity, and to treating cerebral amyloidosis by administering such compounds therapeutically.
2. Description of Related Art
There is no effective therapy for cerebral amyloidosis, which almost invariably has a fatal outcome following the onset of amyloid deposits. For example, Alzheimer's disease is estimated to be the fourth or fifth leading cause of death in North Americans.
A universally accepted indicator of cerebral amyloidosis is the accumulation of lesions, so-called "senile plaques," that are comprised in large part of amyloid fibrils. Senile plaques are spherical, ranging from 10 to 200 .mu.m in diameter, and are found occasionally in aged cerebral cortex (see below) but in larger numbers in Alzheimer-affected cortex.
Most specialists agree that reproduction of amyloid fibrils experimentally from precursor materials which are extracted, activated, or otherwise derived from human brain constitutes the best available evidence linking an agent or precursor to the progression of cerebral amyloidosis. Indeed, the literature has documented the use of such materials from human brain, normal and Alzheimer-affected, that are not already amyloid, and their transformation into amyloid.
Accordingly, a reliable indicator is available for compounds that might be effective in treating cerebral amyloidosis. In particular, it is possible to determine whether a given compound prevents the structural tansition of a brain-localized precursor to a .beta.-pleated sheet conformation and thus prevent conversion to cerebral amyloid (i.e., that displays "anti-amyloid activity") at physiologically acceptable levels of the active agent. See U.S. Pat. No. 5,231,170, the contents of which are incorporated by reference.
In a majority of cases, subjects with cerebral amyloidosis, including Alzheimer's patients, display symptoms on a quantitative basis. Blessed et al., Brit J. Psychiatry 114: 797-811 (1968); Tomlinson et al., J. Neurol. Sci. 7: 331-56 (1968); Tomlinson, B. E., et al., J. Neurol. Sci. 11: 205-42 (1970); Corsellis, MENTAL ILLNESS AND THE AGEING BRAIN, Oxford University Press, London (1962); Corsellis, "Ageing and the Dementias," in GREENFIELD'S NEUROPATHOLOGY 796-848, Edward Arnold, London (1976). Elderly subjects who have a small number of senile plaques are asymptomatic and are categorized by some experts as preclinical, by others as presymptomatic, and by still other authorities as normal variants. In any event, the elderly brain apparently can have a low number of senile plaques and still be categorized as "normal." When the amyloid plaque number is high, however, symptoms of dementia appear. Thus, treatment regimens that prevent the formation of amyloid plaques or that reduce the number or rate of formation of amyloid plaques are useful.
A microscopic structure, the so-called "dense microsphere" (DMS), is found in normal brain and in brain affected by Alzheimer's disease. See Averback, Acta Neuropathol. 61: 148-52 (1983); results confirmed by Hara, J. Neuropath. Exp. Neurol. (1986). Evidence for the existence of dense microspheres comes from microscopic histological section studies of fixed whole brain tissue, where the dense microspheres are seen to have a proteinaceous central region ("DMS protein") surrounded by continuous membrane ("DMS membrane").
The extraction, purification, and characterization of isolated samples of DMS and the use of DMS material have been documented. See, for example, U.S. Pat. Nos. 4,919,915 and 4,816,416, the respective contents of which are incorporated by reference.
DMS disruption is believed to commence after individual DMS reach a threshold size in the elderly or Alzheimer group. Even DMS that have reached the threshold size are quite small, with diameters on the order of approximately 10 microns or less. When the DMS disrupt, constituent protein matter transforms and redistributes to occupy a tissue volume, (anywhere between 10 to 1,000 times larger than the precedent DMS), which comprises a much larger injury focus.